title: Hydrophobicity as a driver of MHC class I antigen processing.
abstract: The forces that drive conversion of nascent protein to major histocompatibility complex (MHC) class I-restricted peptides remain unknown. We explored the fundamental property of overt hydrophobicity as such a driver. Relocation of a membrane glycoprotein to the cytosol via signal sequence ablation resulted in rapid processing of nascent protein not because of the misfolded luminal domain but because of the unembedded transmembrane (TM) domain, which serves as a dose-dependent degradation motif. Dislocation of the TM domain during the natural process of endoplasmic reticulum-associated degradation (ERAD) similarly accelerated peptide production, but in the context of markedly prolonged processing that included nonnascent species. These insights into intracellular proteolytic pathways and their selective contributions to MHC class I-restricted peptide supply, may point to new approaches in rational vaccine design.
authors.affiliation: Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Kuhls
authors.forename: Laurence C
authors.initials: LC
authors.lastname: Eisenlohr
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000502:physiology*; D000950:Antigens, Ly / Q000502:physiology; D003600:Cytosol / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015151:Immunoblotting; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D021382:Protein Sorting Signals
chemical_list: D000950:Antigens, Ly; D015395:Histocompatibility Antigens Class I; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D010446:Peptide Fragments; D021382:Protein Sorting Signals